A Brief Review on the Role of Vesicular Monoamine Transporter2 Inhibitors in Hyperkinetic Movement Disorders

Hyperkinetic movement disorders are a common group of movement abnormalities in children, characterized with repetitive unintended involuntary movements. Major hyperkinetic movements include tremor, tic, dystonia, myoclonus, and chorea. Although a number of drugs have been proven to be beneficial for these abnormalities, some patients may become resistant to conventional treatments. Vesicular monoamine transporter2 (VMAT2) inhibitors (Tetrabenazine, Deutetrabenazine, and Valbenazine) are new agents introduced in the last decade for treating some of movement disorders, in particular tardive dyskinesia, Huntington chorea, and Tourette syndrome. In this brief review, we discussed the role of these drugs in managing hyperkinetic movement disorders.


Introduction
Iran J Child Neurol. Summer 2021 Vol. 15 No. 3 blocking dopamine receptors by neuroleptics is the most effective and first-line therapy in these conditions. However, these drugs have potentially serious side effects such as Tardive dyskinesia (TD) (3) which is a rare permanent movement disorder due to the prolonged use of dopamine receptor blockers, especially neuroleptics (4). This disorder presents with involuntary movements of the face and tongue, such as continues chewing and tongue protrusion or thrust, along with choreiform movements of extremities (5).  In 2008, tetrabenazine was approved by the FDA for managing chorea in patients with Huntington disease (HD) (6,7). There are two types of these transporters: VMAT1, which is present in both the peripheral and central nervous systems, and VMAT2, which has been localized only in presynaptic neurons (8) Also, tetrabenazine has been used as an off-label medication for treating Tourette's disorder and TD (4). There are a few studies on the application of VMAT 2 inhibitors in children with hyperkinetic movement disorders. In this brief review, we intend to describe these new drugs and discuss their roles in treating hyperkinetic movement disorders in pediatrics.

Drug Description
Tetrabenazine (TBZ) was initially introduced in the 1950s as an antipsychotic agent (6). This drug was the first VMAT 2 inhibitor approved by the FDA in 2008 to treat HD-induced chorea (7,8). Tetrabenazine binds to type 2 vesicular monoamine transporters (VMAT 2 ) and inhibits the entry of dopamine molecules into these vesicles, depleting their dopamine content. So, the drug is also known as a dopamine depletion agent. The VMAT-2 is found mainly in the central nervous system and transports serotonin, dopamine, norepinephrine, and histamine into vesicles for storage. Tetrabenazine depletes dopamine more selectively compared to other monoamines (9, 10).
In the liver, the drug is extensively metabolized to its primary active metabolite (alphadihydrotetrabenazine) by the CYP2D6 enzyme.
The half-life of alpha-dihydrotetrabenazine is three to eight hours (11,12). At high doses, TBZ also blocks postsynaptic dopamine receptors (i.e., a dopamine receptor blocker (DRB)) (8). This drug is an oral benzoquinoline derivative and is generally considered to be well-tolerated (13). In different studies, TBZ has been noted to be highly effective for treating HD-associated chorea (13)(14)(15). Also, this drug has been effective in the treatment of some other hyperkinetic movement disorders such as tics and dystonia. Tetrabenazine is also used to control motor and phonic tics in children and adolescents with Tourette syndrome (TS). In a relatively old  (5,8,18). Since 2017, two newer VMAT 2 inhibitors have been approved by the FDA for managing some hyperkinetic movement disorders such as chorea (especially in patients with HD) and tics (especially in those suffering from TS) (8,19,20).

Deutetrabenazine (DBZ) was the first novel medication categorized under VMAT 2 inhibitors.
A chemical substance in DBZ, named deuterium, reduces the drug's metabolic rate and thus increases its half-life. Deutetrabenazine is an isotopic isomer of TBZ, resulting from the replacement of two methoxy groups (-OCH3) with two trideuteromethoxy groups (-OCD3) at the 9 and 10 positions, which reduces the side effects of DBZ (21). On the other hand, lower serum level fluctuations of this drug reduce its neuropsychiatric side effects such as depression and akathisia (19,21,22). Deutetrabenazine is an effective and safe VMAT 2 inhibitor for treating tardive dyskinesia and HD in adults and adolescents (23). In one open-label trial, DBZ at the doses of 18 to 36 mg/ day decreased the severity of tics in adolescents with TS. Irritability, fatigue, and headache were reported as the side effects of DBZ in this study (24).  (25). In contrast to TBZ and even DBZ, VBZ has not been associated with increased risk of suicidal thinking and behaviors in adults (27). However, VBZ may increase the QT interval, so it is not recommended to be used by patients with prolonged QT intervals (28). Some randomized clinical trials were conducted on the efficacy and safety of VBZ in adult patients with tardive dyskinesia; almost all of them reported improvements in dyskinetic movements (20).
Recently, these drugs, as a second-line option after clonidine, have been used for managing TS. Today, VMAT2 inhibitors are superior to neuroleptics for controlling chronic and severe tics (29,30).